Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans as analgesic agents

ABSTRACT

Hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyrans useful as analgesic agents, derivatives thereof, intermediates therefor and processes for their preparation.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain6a,7,8,9,10,10a-hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]pyransand derivatives thereof useful as CNS agents, especially as analgesicsand tranquilizers, in mammals, including man; and to intermediatestherefor.

2. Description of the Prior Art

The search for new and improved analgesic agents has, for the pastseveral years, centered upon cannabinol-type compounds. Large numbers ofderivatives of such compounds and modification of the basicdibenzo[b,d]pyran ring system common to such compounds have beendescribed in the literature. Several review articles have appeared whichcontain extensive bibliographies to the synthesis, structure, andbiological properties of the naturally-occurring dibenzo[b,d]pyrans aswell as to derivates and modifications thereof. Of particular interestare the following review articles: R. Mechoulam, Ed., "Marijuana.Chemistry, Pharmacology, Metabolism and Clinical Effects", AcademicPress, New York, N.Y. 1973; Mechoulam, et al., Chemical Reviews, 76,75-112 (1976). In addition to these review articles from the chemicalliterature, rather comprehensive reviews appear in U.S. Pat. Nos.3,886,184 and 3,968,125. However, despite the large numbers of suchcompounds described in the literature, the search for new and improvedagents continues thus pointing to the lack of an agent useful for thecontrol of broad levels of pain and accompanied by a minimum ofside-effects.

U.S. Pat. No. 3,968,125, issued July 6, 1976, describes a series of6a,7,8,9,10,10a-hexahydro-1-hydroxy-3-alkyl-6H-dibenzo[b,d]pyran-9-olsuseful as hypotensive agents, as psychotropic drugs, particularly asanti-anxiety and/or antidepressant drugs, and as sedative and/oranalgesic drugs.

Mechoulam, Ed., "Marijuana. Chemistry, Pharmacology, Metabolism andClinical Effects", Academic Press, New York, N.Y., 1973, at page 58,describes6a,7,8,10a-tetrahydro-1-hydroxy-3-alkyl-6,6-dimethyl-9-hydroxymethyl-6H-dibenzo[b,d]pyranand6a,7,10,10a-tetrahydro-1-hydroxy-3alkyl-6,6-dimethyl-9-hydroxymethyl-6H-dibenzo[b,d]pyran,which are metabolites of the corresponding tetrahydrocannabinols havinga methyl group at the 9-position.

In addition to the problem of addiction liability, the opiate analgesicshave a limited use in the treatment of chronic pain states such ascancer because tolerance to the analgesic activity is developed uponrepeated administration of these drugs. While the potent9-hydroxy-dibenzo[b,d]pyran analgesics represent a therapeutic advancesince they are non-narcotic drugs, it has been found that rapidtolerance develops to their analgesic action thereby limiting the use ofthese agents in chronic pain states where repeated dosing over longperiods of time is necessary to provide continued pain relief.

SUMMARY OF THE INVENTION

It has now been found that certain6a,7,8,9,10,10a-hexahydro-1-hydroxy-9-hydroxymethyl-3-substituted-6H-dibenzo[b,d]-pyransand derivatives thereof having formula I below are effective as CNSagents, especially as analgesics and tranquilizers, which arenon-narcotic and free of addiction liability. In addition, significantlyless tolerance is exhibited to the analgesic activity of these compoundsthan, for example, the compounds wherein the 9-position bears a hydroxygroup in place of the hydroxymethyl group, thus making them particularlyuseful in the treatment of chronic pain. The compounds have formula Ibelow ##STR1## wherein

R is selected from the group consisting of hydrogen and alkanoyl havingfrom one to five carbon atoms;

R₁ is selected from the group consisting of hydrogen, alkanoyl havingfrom one to five carbon atoms and --CO--(CH₂)_(P) --NR₄ R₅ wherein p is0 or an integer from 1 to 4; each of R₄ and R₅ when taken individuallyis selected from the group consisting of hydrogen and alkyl having fromone to four carbon atoms; R₄ and R₅ when taken together with thenitrogen to which they are attached form a 5- or 6-membered heterocyclicring selected from the group consisting of piperidino, pyrrolo,pyrrolidino, morpholino and N-alkylpiperazino having from one to fourcarbon atoms in the alkyl group;

each of R₂ and R₃ is selected from the group consisting of hydrogen andmethyl;

Z is selected from the group consisting of

(a) alkylene having from one to ten carbon atoms;

(b) --(alk₁)_(m) --O--(alk₂)_(n) -- wherein each of (alk₁) and (alk₂) isalkylene having from one to ten carbon atoms, with the proviso that thesummation of carbon atoms in (alk₁) plus (alk₂) is not greater than ten;each of m and n is 0 or 1; and

W is selected from the group consisting of hydrogen, pyridyl and##STR2## wherein W₁ is selected from the group consisting of hydrogen,fluoro and chloro;

and the pharmaceutically acceptable acid addition salts of thosecompounds wherein R₁ is CO--(CH₂)_(p) --NR₄ R₅ and/or W is pyridyl.

Also included in this invention are various derivatives of saidcompounds which are useful as dosage forms and intermediates therefor.Among such derivatives are the pharmaceutically acceptable acid additionsalts of compounds of formula I. Representative of such salts aremineral acid salts such as the hydrochloride, hydrobromide, sulfate,nitrate, phosphate; organic acid salts such as the citrate, acetate,sulfosalicylate, tartrate, glycolate, malonate, maleate, fumarate,malate, 2-hydroxy-3-naphthoate, pamoate, salicylate, stearate,phthalate, succinate, gluconate, mandelate, lactate and methanesulfonate.

Compounds having formula I contain asymmetric centers at the 6a-and/or10a-positions. There may be additional asymmetric centers in the3-position substituent (-Z-W), and 5-, 6- and 9-positions. Diastereomerswith the 9β-configuration are generally favored over the 9α-isomersbecause of greater (quantitatively) biological activity. For the samereason, the trans(6a,10a)diastereomers are generally favored over thecis(6a,10a)diastereomers. Among the enantiomers of a given compound, onewill generally be favored over the other and the racemate because of itsgreater activity. The enantiomer favored is determined by the proceduresdescribed herein. For convenience, the above formula depicts the racemiccompounds. However, the above formula is considered to be generic to andembracive of the racemic modifications of the compounds of thisinvention, the diastereomeric mixtures, the pure enantiomers anddiastereomers thereof. The utility of the racemic mixtures, thediastereomeric mixtures as well as of the pure enantiomers anddiastereomers, is determined by the biological evaluations describedbelow.

Further, various intermediates useful in the preparation of compoundshaving formula I are also included in this invention. The intermediateshave the formula: ##STR3## wherein R₂, R₃ and Z are as described aboveand W' is selected from the group consisting of pyridyl and ##STR4##wherein

W₁ is selected from the group consisting of hydrogen, fluoro and chloro;

and the pharmaceutically acceptable acid addition salts of thosecompounds wherein R₁ is --CO--(CH₂)_(p) --NR₄ R₅ and/or W is pyridyl.

Asymmetric centers may exist in compounds of formula II at all positionspreviously noted with respect to formula I except, of course, at the9-position.

The favored compounds of this invention are those wherein thehydroxymethyl group at the 9-position has the β-configuration. Suchcompounds are of greater potency and efficacy than are the correspondingα-compounds. Of special interest are compounds of formula I wherein theseveral variables have the significance shown below in Table A:

                                      TABLE A                                     __________________________________________________________________________    R     R.sub.2                                                                             R.sub.2                                                                            R.sub.3                                                                            Z       m n W                                           __________________________________________________________________________    H, COCH.sub.3                                                                       H, COCH.sub.3                                                                       H, CH.sub.3                                                                        H, CH.sub.3                                                                        alkylene having                                                                       --                                                                              --                                                                              H                                                                 4 to 9 carbon                                                                 atoms                                                   H, COCH.sub.3                                                                       H, COCH.sub.3                                                                       H, CH.sub.3                                                                        H, CH.sub.3                                                                        alkylene having                                                                       --                                                                              --                                                                              C.sub.6 H.sub.5                                                   4 to 6 carbon                                                                             pyridyl                                                           atoms                                                   H, COCH.sub.3                                                                       H, COCH.sub.3                                                                       H, CH.sub.3                                                                        H, CH.sub.3                                                                        (alk.sub.1).sub.m --0--                                                               0 1 H, C.sub.6 H.sub.5                                                (alk.sub.2).sub.n                                       __________________________________________________________________________

Particularly favored because of their greater potency are thosecompounds of formula I, Table A, wherein the variables have thesignificance shown in Table B below:

                  TABLE B                                                         ______________________________________                                        R   R.sub.1                                                                             R.sub.2                                                                              R.sub.3  Z           m   n   W                               ______________________________________                                        H   H     CH.sub.3                                                                             CH.sub.3                                                                            (CH.sub.2).sub.5                                                                             --  --  H                                         H      CH.sub.3                                                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                           --  --  H                                         H      CH.sub.3                                                                            CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                     --  --  H                               H   H     CH.sub.3                                                                             CH.sub.3                                                                            CH(CH.sub.3)(CH.sub.2).sub.3                                                                 --  --  C.sub.6 H.sub.5                 H   H     CH.sub.3                                                                             CH.sub.3                                                                            OCH(CH.sub.3)(CH.sub.2).sub.3                                                                0   1   C.sub.6 H.sub.5                 H   H     CH.sub.3                                                                             CH.sub.3                                                                            OCH(CH.sub.3)(CH.sub.2).sub.5                                                                0   1   H                               H   H     H      CH.sub.3                                                                            OCH(CH.sub.3)(CH.sub.2).sub.3                                                                0   1   C.sub.6 H.sub.5                 ______________________________________                                    

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are readily prepared from thecorresponding 9-oxo compounds having formula III below: ##STR5## whereinR, R₂, R₃, Z and W are as defined above via the Wittig reaction withmethylene triphenylphosphorane or other appropriate methylide. The usualprocedure comprises generating the Wittig reagent; that is, themethylide, in situ and, immediately following generation of themethylide, reacting it with the appropriate 9-oxo compound. A convenientprocedure for generating the methylide comprises reacting sodium hydridewith dimethyl sulfoxide at a temperature of from about 50° C.-80° C.,usually until evolution of hydrogen ceases, followed by reacting theresulting solution of methyl sulfinyl carbanion with, for example,methyl triphenyl phosphonium bromide at a temperature of from about 10°C. to about 80° C. To the thus-produced solution of the ylide is thenadded the appropriate 9-oxo compound and the mixture stirred attemperatures ranging from about room temperature to 80° C. The9-methylene compound thus produced is isolated by known procedures.Fahrenholtz, U.S. Pat. No. 3,636,058, reports the preparation of several6a,7,8,9,10,10a-hexahydro-1-hydroxy-3-alkyl-6,6-dimethyl-9-methylene-6H-dibenzo[b,d]pyrans.

Other methods of generating the methylide are, of course, known and canbe used in lieu of the above-described procedure. Typical procedures aredescribed by Maercker, Organic Reactions, 14, 270 (1965).

In compounds having formula III, the hydroxy group at the 1-position canbe protected if desired as, for example, by conversion to an alkanoyloxyderivative. Other protecting groups can, of course, be used. Thehydroxyl group can be converted to ethers such as, for example,tetrahydropyranyl ethers. However, protection of the hydroxy group isnot absolutely necessary if sufficient base is present to convert thehydroxy group to an alkoxide.

The 9-methylene compounds are then converted to correspondinghydroxymethyl derivatives by hydroboration-oxidation. A convenientprocedure and one favored for the hydroboration step comprises reactingthe 9-methylene compound with borane in tetrahydrofuran at temperaturesfrom about -10° C. to about room temperature. The temperature is notcritical. However, temperatures within the range indicated above producesatisfactory yields. The reaction is generally conducted intetrahydrofuran or diethylene glycol dimethyl ether (diglyme). Theborane is conveniently used as the borane-tetrahydrofuran complexbecause of its availability and stability. The borane product is notisolated but is directly oxidized to the desired hydroxymethyl compound.A typical procedure comprises decomposing the excess borane by additionof water and then adding a suitable base such as sodium acetate, andusually a small excess of hydrogen peroxide. The oxidation is conductedat temperatures from about -10° to about 50° C. and the productrecovered by known procedures.

In the Wittig reaction, as noted above, the 1-hydroxy group can beprotected by appropriate means as by formation of an alkanoyl derivativethereof. The Wittig reaction results in removal of this protecting groupto regenerate the 1-hydroxy group. It is not necessary to re-protect the1-hydroxy group for the subsequent hydroboration-oxidation procedure.

The necessary 6a,7,10,10a-tetrahydro-1-hydroxy-6,6-R₂ R₃-3-substituted-6H-dibenzo[b,d]pyran-9(8H)-ones are known compoundsdescribed in Dutch specification No. 7612174, in U.S. Pat. No. 3,968,125and by R. Mechoulam, Ed., "Marijuana. Chemistry, Pharmacology,Metabolism and Clinical Effects", Academic Press, New York, N.Y. (1973),pages 45, 46 and 56. Esters of compounds of formula I wherein R₁ isalkanoyl or --CO--(CH₂)_(p) --NR₄ R₅ are readily prepared by reactingformula I compounds with the appropriate alkanoic acid or acid offormula HOOC--(CH₂)_(p) --NR₄ R₅ in the presence of a condensing agentsuch as dicyclohexylcarbodiimide. Alternatively, they are prepared byreaction of a formula I compound with the appropriate alkanoic acidchloride or anhydride, e.g., acetyl chloride or acetic anhydride, in thepresence of a base such as pyridine.

Esters in which each of the R and R₁ groups is esterified are preparedby acylation according to the above-described procedures. Compounds inwhich only the 9-hydroxymethyl group is acylated are obtained by mildhydrolysis of the corresponding diacyl derivative, advantage being takenof the greater ease of hydrolysis of the phenolic acyl group. Thethus-produced formula I compounds bearing 1-hydroxy-9-acyl substitutioncan then be acylated further with a different acylating agent to producea diesterified compound in which the ester group at the 1- and the9-positions are different.

The presence of a basic group in the ester moiety (OR₁) of the compoundsof this invention permits formation of acid-addition salts involvingsaid basic group. When the herein described basic esters are preparedvia condensation of the appropriate amino acid hydrochloride (or otheracid addition salt ) with the appropriate compound of formula I in thepresence of a condensing agent, the hydrochloride salt of the basicester is produced. Careful neutralization affords the free base. Thefree base form can then be converted to other acid addition salts byknown procedures.

Acid addition salts can, of course, as those skilled in the art willrecognize, be formed with formula I compounds wherein --Z--W contains abasic group. Such salts are prepared by standard procedures. The basicester derivatives are, of course, able to form mono- or di-acid additionsalts because of their dibasic functionality.

The analgesic properties of the compounds of this invention aredetermined by tests using nociceptive stimuli.

Tests Using Thermal Nociceptive Stimuli

(a) Mouse Hot Plate Analgesic Testing

The method used is modified after Woolfe and MacDonald, J. Pharmacol.Exp. Ther., 80, 300-307 (1944). A controlled heat stimulus is applied tothe feet of mice on a 1/8" thick aluminum plate. A 250 watt reflectorinfrared heat lamp is placed under the bottom of the aluminum plate. Athermal regulator, connected to thermistors on the plate surface,programs the heat lamp to maintain a constant temperature of 57° C. Eachmouse is dropped into a glass cylinder (61/2" diameter) resting on thehot plate, and timing is begun when the animal's feet touch the plate.The mouse is observed at 0.5 and 2 hours after treatment with the testcompound for the first "flicking" movements of one or both hind feet, oruntil 10 seconds elapse without such movements. Morphine has an MPE₅₀ =4-5.6 mg./kg. (s.c.).

(b) Mouse Tail Flick Analgesic Testing

Tail flick testing in mice is modified after D'Amour and Smith, J.Pharmacol. Exp. Ther., 72, 74-79 (1941) using controlled high intensityheat applied to the tail. Each mouse is placed in a snug-fitting metalcylinder, with the tail protruding through one end. This cylinder isarranged so that the tail lies flat over a concealed heat lamp. At theonset of testing, an aluminum flag over the lamp is drawn back, allowingthe light beam to pass through the slit and focus onto the end of thefail. A timer is simultaneously activated. The latency of a sudden flickof the tail is ascertained. Untreated mice usually react within 3-4seconds after exposure to the lamp. The end point for protection is 10seconds. Each mouse is tested at 0.5 and 2 hours after treatment withmorphine and the test compound. Morphine has an MPE₅₀ of 3.2-5.6 mg./kg.(s.c.).

(c) Tail Immersion Procedure

The method is a modification of the receptacle procedure developed byBenbasset, et al., Arch. int. Pharmacodyn., 122, 434 (1959). Male albinomice (19-21 g.) of the Charles River CD-1 strain are weighed and markedfor identification. Five animals are normally used in each drugtreatment group with each animal serving as its own control. For generalscreening purposes, new test agents are first administered at a dose of56 mg./kg. intraperitoneally or subcutaneously, delivered in a volume of10 ml./kg. Preceding drug treatment and at 0.5 and 2 hours post drug,each animal is placed in the cylinder. Each cylinder is provided withholes to allow for adequate ventilation and is closed by a round nylonplug through which the animal's tail protrudes. The cylinder is held inan upright position and the tail is completely immersed in the constanttemperature waterbath (56° C.). The endpoint for each trial is anenergetic jerk or twitch of the tail coupled with a motor response. Insome cases, the endpoint may be less vigorous post drug. To preventundue tissue damage, the trial is terminated and the tail removed fromthe waterbath within 10 seconds. The response latency is recorded inseconds to the nearest 0.5 second. A vehicle control and a standard ofknown potency are tested concurrently with screening candidates. If theactivity of a test agent has not returned to baseline values at the2-hour testing point, response latencies are determined at 4 and 6hours. A final measurement is made at 24 hours if activity is stillobserved at the end of the test day.

Test Using Chemical Nociceptive Stimuli

Suppression of Phenylbenzoquinone Irritant-Induced Writhing

Groups of 5 Carworth Farms CF-1 mice are pretreated subcutaneously ororally with saline, morphine, codeine or the test compound. Twentyminutes (if treated subcutaneously) or fifty minutes (if treated orally)later, each group is treated with intraperitoneal injection ofphenylbenzoquinone, an irritant known to produce abdominal contractions.The mice are observed for 5 minutes for the presence or absence ofwrithing starting 5 minutes after the injection of the irritant. MPE₅₀'s of the drug pretreatments in blocking writhing are ascertained.

Tests Using Pressure Nociceptive Stimuli

Effect on the Haffner Tail Pinch Procedure

A modification of the procedure of Haffner, Experimentelle PrufungSchmerzstillender. Mittel Deutch Med. Wschr., 55, 731-732 (1929) is usedto ascertain the effects of the test compound on aggressive attackingresponses elicited by a stimulus pinching the tail. Male albino rats(50-60 g.) of the Charles River (Sprague-Dawley) CD strain are used.Prior to drug treatment, and again at 0.5, 1, 2, and 3 hours aftertreatment, a Johns Hopkins 2.5-inch "bulldog" clamp is clamped onto theroot of the rat's tail. The endpoint at each trial is clear attackingand biting behavior directed toward the offending stimulus, with thelatency for attack recorded in seconds. The clamp is removed in 30seconds if attacking has not yet occurred, and the latency of responseis recorded as 30 seconds. Morphine is active at 17.8 mg./kg. (i.p.).

Tests Using Electrical Nociceptive Stimuli

The "Flinch-Jump" Test

A modification of the flinch-jump procedure of Tenen,Psychopharmacologia, 12, 278-285 (1968) is used for determining painthresholds. Male albino rats (175-200 g.) of the Charles River(Sprague-Dawley) CD strain are used. Prior to receiving the drug, thefeet of each rat are dipped into a 20% glycerol/saline solution. Theanimals are then placed in a chamber and presented with a series of1-second shocks to the feet which are delivered in increasing intensityat 30-second intervals. These intensities are 0.26, 0.39, 0.52, 0.78,1.05, 1.31, 1.58, 1.86, 2.13, 2.42, 2.72 and 3.04 mA. Each animal'sbehavior is rated for the presence of (a) flinch, (b) squeak and (c)jump or rapid forward movement at shock onset. Single upward series ofshock intensities are presented to each rat just prior to, and at 0.5,2, 4 and 24 hours subsequent to drug treatment.

Results of the above tests are recorded as percent maximum possibleeffect (% MPE). The % MPE of each group is statistically compared to the% MPE of the standard and the predrug control values. The % MPE iscalculated as follows: ##EQU1##

The compounds of the present invention are active analgesics via oraland parenteral administration and are conveniently administered incomposition form. Such compositions include a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice. For example, they may be administered in theform of tablets, pills, powders or granules containing such excipientsas starch, milk sugar, certain types of clay, etc. They may beadministered in capsules, in admixtures with the same or equivalentexcipients. They may also be administered in the form of oralsuspensions, solutions, emulsions, syrups and elixirs which may containflavoring and coloring agents. For oral administration of thetherapeutic agents of this invention, tablets or capsules containingfrom about 0.01 to about 100 mg. are suitable for most applications.

The physician will determine the dosage which will be most suitable foran individual patient and it will vary with the age, weight and responseof the particular patient and the route of administration. Generally,however, the initial analgesic dosage in adults may range from 0.01 to500 mg. per day in single or divided doses. In many instances, it is notnecessary to exceed 100 mg. daily. The favored oral dosage range is fromabout 0.01 to about 300 mg./day; the preferred range is from about 0.10to about 50 mg./day. The favored parenteral dose is from about 0.01 toabout 100 mg./day; the preferred range from about 0.01 to about 20mg./day.

EXAMPLE 1dl-6aβ,7,10,10aα-Tetrahydro-1-acetoxy-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran-9(8H)-one

To a solution ofdl-6aβ,7,10,10aα-tetrahydro-1-hydroxy-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran-9(8H)-one(4.06 gm., 10 mmoles) dissolved at 0° C. in 15 ml. pyridine is added 15ml. (excess) acetic anhydride and the resultant solution is stirred atice temperatures for 30 minutes. The mixture is poured onto ice/water(100 ml.), neutralized with dilute HCl and extracted with ethyl acetate(2 × 100 ml.). The pooled organic layers are washed with water (1 × 50ml.), brine (1 × 50 ml.), dried over MgSO₄, filtered and evaporatedunder reduced pressure. Crystals are obtained from ether/pentane (1:1)to afford 3.43 gm. (76%) of the title compound, m.p. 95.5°-97° C.

TLC system: pentane/ether (1:1) R_(f) 0.2

IR (KBr) 2.95μ (W), 3.40 (M), 5.62 (S), 5.72 (S), 6.12 (S), 6.31 (S),6.70 (S).

Analysis: Calc'd for C₂₈ H₃₄ O₅ : C, 74.64; H, 7.61%. Found: C, 74.55;H, 7.59%.

¹ H NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 7.22 (s, 5H), 6.26 (d,1H), 6.18 (d, 1H), 4.0-4.5 (m, 1H), 2.22 (s, 3H), 1.48 (s, 3H), 1.22 (d,3H), 1.04 (s, 3H), 3.0-3.55 (m, 2H), 2.40-2.80 (m, 2H), 1.42-2.20 (m,4H).

EXAMPLE 2dl-6aβ,7,8,9,10,10aα-Hexahydro-1-hydroxy-6,6-dimethyl-9-methylene-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran

To 50% sodium hydride/mineral oil (1.52 gm., 32 mmoles), (washed 3 × 25ml. portions of pentane) is added 60 ml. of dry dimethylsulfoxide andthe mixture heated at 50° C. for 2.5 hours. The heterogeneous mixtureturns homogeneous during this heating period. 11.86 (34 mmoles) ofmethyl triphenylphosphonium bromide is then added in one portion. Theyellow solution is heated at 63°-65° C. for 2.5 hours and 1.89 g. (4.2mmoles) ofdl-6aβ,7,10,10aα-tetrahydro-1-acetoxy-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]-pyran-9(8H)-onedissolved in 60 ml. of dimethysulfoxide is added all at once and heatedat 63°-65° C. for an additional 1.5 hours. The reaction is then pouredonto 150 ml. ice water/25 g. NaHCO₃ and extracted 2 × 50 ml. with ether.The combined ether extracts are dried over MgSO₄ , decolorized withcharcoal and filtered through a bed of silica gel to afford a colorlessoil which is chromatographed on 50 g. silica gel (eluting solventcyclohexane). A non-polar impurity is eluted first, then the polarity ofthe solvent is increased to ether/cyclohexane (1:10) thus affording1.099 gm. (64.1%) of the title product as a colorless oil.

IR (smear) 2.80μ (w), 3.00 (w), 3.40 (s), 3.48 (s), 6.17 (s), 6.27 (s).

Mass Spec. M⁺ 406 (100%), 391 (12%), 260 (40%), 244 (40%).

TLC: Brinkman Plate Benzene/Ether (1:1) R_(f) 0.9

¹ H NMR (60 MHz) δ_(CDCl).sbsb.3^(TMS) (ppm): 7.18 (s, 5H), 5.98 (d,1H), 5.79 (d, 1H), 5.67 (s, 1H), 3.9-4.4 (m, 1H), 3.5-4.9 (m, 4H), 1.38(s, 3H, CHCl₃), 1.2 (d, 3H), 1.05 (s, 3H).

EXAMPLE 3dl-6aβ,7,8,9,10,10aα-Hexahydro-1-hydroxy-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy]-6H-dibenzo[b,d]pyran

A solution of 0.849 g.dl-6aβ,7,8,10,10aα-pentahydro-1-hydroxy-6,6-dimethyl-9-methylene-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran(2 mmoles) dissolved in 20 ml. of dry tetrahydrofuran is cooled to 0° C.in an ice/water bath. Borane-tetrahydrofuran complex (3.0 ml., 3 mmoles,1M solution) is added and the colorless solution allowed to stirovernight at ambient temperature (18 hours). The mixture is cooled inice and 5 ml. of water added to decompose the excess reagent. It isstirred for 15 minutes and then 2 ml. (6 mmoles) of 3N sodium acetatefollowed by 2 ml. 30% hydrogen peroxide added. It is stirred at 0° C.for 15 minutes then allowed to warm to room temperature and stirredovernight (24 hours). The reaction mixture is poured onto 100 ml.ice/water and then extracted with 2 × 50 ml. ether. The combined etherextracts are washed with sodium sulfite until negative to starch KItest, dried over MgSO₄ and evaporated to dryness to yield a pale yellowoil which is chromatographed on 35 g. Brinkman silica gel (elutingsolvent cyclohexane/ether 3:1) to afford a colorless foam weighing 364mg. (43%).

IR (KBr) 2.95μ (s), 3.40 (s), 6.17 (s), 6.30 (s).

Mass Spec. 424 (100%), 278 (79%), 279 (41%), 236 (29%).

Analysis: Calc'd for C₂₇ H₃₆ O₄ : C, 76.38; H, 8.55%. Found: C, 75.73;H, 8.77%.

EXAMPLE 4dl-6aβ,7,8,9,10,10aα-Hexahydro-1-hydroxy-9β-acetoxymethyl-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran

A solution of 0.1 mole ofdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyranin 100 ml. of acetonitrile is treated with 0.1 mole of acetic anhydrideand the mixture heated for 12 hours under nitrogen. It is then pouredonto ice/water and extracted with ethyl acetate (2 × 100 ml.), theextracts combined, washed with brine and dried (MgSO₄). Evaporationunder reduced pressure followed by silica gel chromatography affords thetitle product as an oil.

Similarly, substitution of anhydrides of propionic, butyric and valericacid for acetic anhydride affords the corresponding ester derivatives.

EXAMPLE 5

The following compounds are similarly prepared according to theprocedures of Examples 1-3 but using the appropriate 9-oxo compound asreactant.

    __________________________________________________________________________     ##STR6##                                                                     CH.sub.2   6a,                                                                OH   R.sub.2                                                                          R.sub.3                                                                          10a   Z              W                                             __________________________________________________________________________    β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.3                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              CH(CH.sub.3)(CH.sub.2).sub.3                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.4                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              CH(CH.sub.3)(CH.sub.2).sub.4                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH.sub.2 CH.sub.2                                                                            C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.2                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              CH(CH.sub.3)(CH.sub.2).sub.2                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.3O                                                                C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.3                                                                 4-pyridyl                                        β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)CH.sub.2O(CH.sub.2).sub.2                                                        C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              CH(CH.sub.3)CH.sub.2O(CH.sub.2).sub.2                                                        C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            OCH(CH.sub.3)(CH.sub.2).sub.5                                                                H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              OCH(CH.sub.3)(CH.sub.2).sub.5                                                                H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            OCH(CH.sub.3)(CH.sub.2).sub.3                                                                C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              OCH(CH.sub.3)(CH.sub.2).sub.3                                                                C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            OCH(CH.sub.3)(CH.sub.2).sub.2                                                                C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              OCH(CH.sub.3)(CH.sub.2).sub.2                                                                C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            O              C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            (CH.sub.2).sub. 5                                                                            H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              (CH.sub.2).sub.5                                                                             H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.2O                                                                C.sub.6 H.sub.5                                  β                                                                             H  CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.3                                                                 C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2).sub.5                                                     H                                                β                                                                             H  CH.sub.3                                                                         trans                                                                            (CH.sub.2).sub.7                                                                             C.sub.6 H.sub.5                                  β                                                                             H  CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)CH.sub.2                                                                         2-pyridyl                                        β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            (CH.sub.2).sub.3                                                                             3-pyridyl                                        β                                                                             H  H  trans                                                                            (CH.sub.2).sub.2                                                                             4-pyridyl                                        β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            C(CH.sub.3).sub.2 CH.sub.2                                                                   H                                                β                                                                             CH.sub.3                                                                         H  trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.2                                                                 4-FC.sub.6 H.sub.4                               β                                                                             CH.sub.3                                                                         H  trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.2                                                                 4-ClC.sub.6 H.sub.4                              β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            O              C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              O              4-FC.sub.6 H.sub.4                               β                                                                             CH.sub.3                                                                         H  trans                                                                            OCH(CH.sub.3)(CH.sub.2).sub.6                                                                H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            O              4-ClC.sub.6 H.sub.4                              β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            O              2-pyridyl                                        β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            O              4-pyridyl                                        β                                                                             H  H  trans                                                                            OCH(CH.sub.3)(CH.sub.2).sub.3                                                                2-pyridyl                                        β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                           H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              C(CH.sub.3).sub.2 (CH.sub.2).sub.6                                                           H                                                α                                                                            CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.3                                                                 C.sub.6 H.sub.5                                  α                                                                            CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              CH(CH.sub.3)(CH.sub.2).sub.4                                                                 C.sub.6 H.sub.5                                  α                                                                            CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            OCH(CH.sub.3)(CH.sub.2).sub.5                                                                H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH.sub.2       H                                                β                                                                             H  CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.9                                                                 H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            (CH.sub.2).sub.10                                                                            H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.2 O                                                               C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH.sub.2 CH(CH.sub.3)OCH(CH.sub.3)CH.sub.2                                                   C.sub.6 H.sub. 5                                 β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         cis                                                                              (CH.sub.2).sub.3 OCH.sub.2                                                                   H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            (CH.sub.2)O(CH.sub.2).sub.3                                                                  H                                                β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            CH(CH.sub.3)(CH.sub.2).sub.2 O(CH.sub.2).sub.4                                               C.sub.6 H.sub.5                                  β                                                                             CH.sub.3                                                                         CH.sub.3                                                                         trans                                                                            (CH.sub.2).sub.4 O(CH.sub.2).sub.5                                                           4-ClC.sub.6 H.sub.4                              __________________________________________________________________________

The above compounds are converted to their diester derivatives by theprocedure of Example 4.

EXAMPLE 6dl-6aβ,7,8,9,10,10aα-Hexahydro-1-acetoxy-6,6-dimethyl-9β-acetoxymethyl-3-[2-(5-phenylpentyloxy]-6H-dibenzo[b,d]pyran

A mixture of 1.0 g. ofdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy]-6H-dibenzo[b,d]pyranand a 5-fold excess of acetic anhydride and pyridine is stirredovernight at room temperature. It is then poured into ice water, theaqueous mixture extracted with ether (3 × 100 ml.) and the combinedextracts washed with water, brine, then dried (MgSO₄) and evaporated.The residue is subjected to column chromatography on silica gel,benzene/ether [9:1] as eluting solvent, to give the title product.

Similarly, replacement of acetic anhydride with the anhydrides ofpropionic, butyric and valeric acids affords the corresponding diestersas their HCl salts.

EXAMPLE 7dl-6aβ,7,8,9,10,10aα-Hexahydro-1-(4-morpholinobutyryloxy)-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyranhydrochloride

Dicyclohexylcarbodiimide (0.227 g., 1.1 mmole) and 4-N-piperidylbutyricacid hydrochloride (0.222 g., 1.0 mmole) are added to a solution ofdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran(0.424 g., 1.0 mmole) in methylene chloride (25 ml.) at roomtemperature. The mixture is stirred for 18 hours and is then cooled to0° C. and filtered. Evaporation of the filtrate affords the titleproduct.

Similarly, the reactant of this example and the compounds of Example 5are converted to the basic esters of the hydroxy group at the 1-positionby reaction with the appropriate basic acid reactant. Esters wherein theR₁ moiety has the following values are thus prepared as theirhydrochloride salts:

--CON(CH₃)₂

--coch₂ nh₂

--co(ch₂)₂ n(c₄ h₉)₂

--co(ch₂)₂ -n-(methyl)piperazino

--COC(CH₃)₂ (CH₂)₂ -piperidino

--CO(CH₂)₃ N(C₂ H₅)₂

--coch(ch₃)(ch₂)₂ -morpholino

--CO(CH₂)₃ -pyrrolo

--CO(CH₂)₃ -pyrrolidino

--COCH₂ -pyrrolo

--CO-morpholino

--CO-piperidino

--CO(CH₂)₄ NH₂

--con(c₄ h₉)₂

--co(ch₂)₃ nh(c₃ h₇)

--co(ch₂)₂ -n-butylpiperazino

Careful neutralization with sodium hydroxide affords the free basicesters.

EXAMPLE 8dl-6aβ,7,8,9,10,10aα-Hexahydro-1-(4:morpholinobutyryloxy)-9.beta.-acetoxymethyl-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran

A solution of 2.0 g. of the product of Example 7,dl-6aβ,7,8,9,10,10aα-hexahydro-1-(4-morpholinobutyryloxy)-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran,in 20 ml. of pyridine is treated at 10° C. with 20 ml. acetic anhydrideand the mixture stirred for 18 hours under nitrogen. It is then pouredonto ice/water. The mixture is extracted with ethyl acetate (2 × 100ml.), the extracts combined, washed with water, brine and dried (MgSO₄).Evaporation under reduced pressure affords the title product as an oil.

Similarly, the remaining basic esters of Example 7 are converted tomixed esters. Substitution of anhydrides of propionic, butyric andvaleric acid for acetic anhydride affords the corresponding esterderivatives.

EXAMPLE 9dl-6aβ,7,8,9,10,10aα-Hexahydro-1-acetoxy-9β-hydroxymethyl-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyran

A solution of 0.1 mole ofdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-6,6dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyranin 100 ml. of acetonitrile is treated with 0.1 mole ofacetyl-1,5,5-trimethylhydantoin and then heated at 80° C. for 12 hoursunder nitrogen. Removal of the solvent under reduced pressure andwashing with water affords the title product as an oil.

Similarly, the 1-alkanoyloxy derivative of the compounds of thisinvention are prepared by substitution of the appropriate formula Icompound (R = R₁ = H) in this procedure and by use of the appropriatealkanoyl-1,5,5-trimethylhydantoin acylating agent. (Alkanoyl =propionyl, butyryl and valeryl).

The alkanoyl 1,5,5-trimethylhydantoins are prepared according to theprocedure of Orazi et al., J. Am. Chem. Soc., 91, 2162 (1969).

EXAMPLE 10 General Hydrochloride Salt Formation

Excess hydrogen chloride is added to a solution of the appropriatecompound of formula I wherein W is pyridyl and/or R₁ is a basic estergroup and the resulting precipitate separated and recrystallized from anappropriate solvent, e.g. methanol-ether (1:10).

The remaining compounds of formula I which have a basic group areconverted to their hydrochlorides in like manner.

Similarly, the hydrobromide, sulfate, nitrate, phosphate, acetate,butyrate, citrate, malonate, maleate, fumarate, malate, glycolate,gluconate, lactate, salicylate, sulfosalicylate, succinate, pamoate,tartrate and embonate salts are prepared.

EXAMPLE 11

One hundred mg. ofdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyranare intimately mixed and ground with 900 mg. of starch. The mixture isthen loaded into telescoping gelatin capsules such that each capsulecontains 10 mg. of drug and 90 mg. of starch.

EXAMPLE 12

A tablet base is prepared by blending the ingredients listed below:

    ______________________________________                                        Sucrose                80.3 parts                                             Tapioca starch         13.2 parts                                             Magnesium stearate      6.5 parts                                             ______________________________________                                    

Sufficientdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-6,6-dimethyl-9β-hydroxymethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyranis blended into this base to provide tablets containing 0.1, 0.5, 1, 5,10 and 25 mg. of drug.

EXAMPLE 13

Suspensions ofdl-6aβ,7,8,9,10,10aα-hexahydro-1-hydroxy-9β-acetoxymethyl-6,6-dimethyl-3-[2-(5-phenylpentyloxy)]-6H-dibenzo[b,d]pyranare prepared by adding sufficient amounts of drug to 0.5%methylcellulose to provide suspensions having 0.05, 0.1, 0.5, 1, 5 and10 mg. of drug per ml.

What is claimed is:
 1. A compound having the formula ##STR7## whereineach of R and R₁ is selected from the group consisting of hydrogen andalkanoyl having from one to five carbon atoms;each of R₂ and R₃ isselected from the group consisting of hydrogen and methyl; Z is selectedfrom the group consisting of(a) alkylene having from one to ten carbonatoms and (b) --(alk₁)_(m) --O--(alk₂)_(n) -- wherein each of (alk₁) and(alk₂) is alkylene having from one to ten carbon atoms, with the provisothat the summation of carbon atoms in (alk₁) plus (alk₂) is not greaterthan ten; each of m and n is 0 or 1; and W is ##STR8## wherein W₁ isselected from the group consisting of hydrogen, fluoro and chloro.
 2. Acompound according to claim 1 wherein each of R and R₁ is hydrogen.
 3. Acompound according to claim 2 wherein R₃ is methyl and Z is saidalkylene .
 4. A compound according to claim 3 wherein each of R₂ and R₃is methyl; Z is alkylene having from 4 to 6 carbon atoms, and W is##STR9##
 5. The trans (6a,10a) diastereomer compound according to claim4 wherein Z is --CH(CH₃)(CH₂)₃ -- and --CH₂ OR has the β-configuration.6. A compound according to claim 2 wherein R₃ is methyl and Z is--(alk₁)_(m) --O--(alk₂)_(n) --.
 7. A compound according to claim 6wherein each of R₂ and R₃ is methyl; Z is --O--(alk₂)-- and W is##STR10##
 8. The trans (6a,10a) diastereomer compound according to claim7 wherein Z is --O--CH(CH₃)(CH₂)₃ -- and --CH₂ OR has theβ-configuration.
 9. A compound according to claim 1 wherein each of Rand R₁ is said alkanoyl.